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  • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

• This invention relates generally to compounds having activity as PDE10 inhibitors, and to compositions containing the same, as well as to methods of treating various disorders by administration of such compounds to a warm-blooded animal in need thereof.
• Cyclic nucleotide phosphodiesterases are represented by a large superfamily of enzymes. PDEs are known to possess a modular architecture, with a conserved catalytic domain proximal to the carboxyl terminus, and regulatory domains or motifs often near the amino terminus. The PDE superfamily currently includes more than twenty different genes subgrouped into eleven PDE families (Lugnier, C, "Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.” Pharmacol Ther. 2006 Mar; 109(3):366-98).
• PDE 10 A recently described PDE, PDE 10, was reported simultaneously by three independent groups (Fujishige et al, "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A),” J Biol Chem 1999, 274: 18438-18445; Loughney et al, "Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase," Gene 1999, 234: 109-117; Soderling et al, "Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A," Proc Natl Acad Sci USA 1999, 96:7071-7076).
• PDE10 has the capacity to hydrolyze both cAMP and cGMP; however, the K m for cAMP is approximately 0.05 ⁇ , whereas the K M for cGMP is 3 ⁇ . In addition, the max for cAMP hydrolysis is fivefold lower than for cGMP. Because of these kinetics, cGMP hydrolysis by PDEIO is potently inhibited by cAMP in vitro, suggesting that PDEIO may function as a cAMP-inhibited cGMP phosphodiesterase in vivo. Unlike PDE8 or PDE9, PDEIO is inhibited by IBMX with an IC 50 (50% inhibitory concentration) of 2.6 ⁇ . ⁇ See Soderling and Beavo, "Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions," Current Opinion in Cell Biology, 2000, 12: 174-179.)
• PDE10 contains two amino-terminal domains that are similar to the cGMP- binding domains of PDE2, PDE5 and PDE6, which are domains conserved across a wide variety of proteins. Because of the wide conservation of this domain, it is now referred to as the GAF domain (for the GAF proteins: cGMP binding phosphodiesterases; the cyanobacterial Anabaena adenylyl cyclase; and the Escherichia coli transcriptional regulator fhlA). Although in PDE2, PDE5 and PDE6 the GAF domains bind cGMP, this is probably not the primary function of this domain in all cases ⁇ e.g., E. coli are not thought to synthesize cGMP).
• Inhibitors of the PDE family of enzymes have widely been sought for a broad indication of therapeutic uses.
• Reported therapeutic uses of PDE inhibitors include allergies, obtrusive lung disease, hypertension, renal carcinoma, angina, congestive heart failure, depression and erectile dysfunction (WO 01/41807 A2).
• Other inhibitors of PDE have been disclosed for treatment of ischemic heart conditions (U.S. Pat. No. 5,693,652).
• More specifically, inhibitors of PDE10 have been disclosed for treatment of certain neurological and psychiatric disorders including, Parkinson's disease, Huntington's disease, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders (Patent Publication No. U.S. 2003/0032579).
• PDE10 has been shown to be present at high levels in neurons in areas of the brain that are closely associated with many neurological and psychiatric disorders. By inhibiting PDEIO activity, levels of cAMP and cGMP are increased within neurons, and the ability of these neurons to function properly is thereby improved. Thus, inhibition of PDEIO is believed to be useful in the treatment of a wide variety of conditions or disorders that would benefit from increasing levels of cAMP and cGMP within neurons, including those neurological, psychotic, anxiety and/or movement disorders mentioned above.
• This invention is generally directed to isolated or substantially pure compounds that have activity as PDEIO inhibitors, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same.
• the compounds have the following general structure (I):
• the compounds of this invention have utility over a wide range of therapeutic applications, and may be used to treat a wide variety of conditions or disorders that would benefit from increasing levels of cAMP and cGMP, especially within neurons, including (but not limited to) neurological disorders, such as psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia, delusional disorders, bipolar disorders, post-traumatic stress disorders, drug-induced psychosis, panic disorders, obsessive-compulsive disorders, attention-deficit disorders, disruptive behavior disorders, autism, depression, dementia, cognitive disorders, epilepsy, insomnias, and multiple sclerosis
• neurological disorders such as psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias
• the methods of this invention include administering an effective amount of a compound of the foregoing structures, typically in the form of a pharmaceutical composition, to a mammal in need thereof, including a human.
• a pharmaceutical composition containing one or more compounds of the foregoing structures in combination with a pharmaceutically acceptable carrier or diluent.
• the present invention is directed generally to isolated or substantially pure compounds useful as PDE10 inhibitors, as well as to methods for their preparation and use, and to pharmaceutical compositions comprising the same.
• the PDE10 inhibitors of the present invention have the following structure (I):
• Ri is H, Ci-3 alkyl, hydroxy-Ci-3 alkyl, C 1 -C3 alkoxy, C 1 -3 alkyl hydroxyl, or glucuronidyl-O-Ci-3 alkyl;
• R 2 is H, Ci-3 alkyl, or glucuronidyl
• R3 and R4 are each independently H, C 1 -3 alkyl, or glucuronidyl
• X 0, -OH, or -O-glucuronidyl
• Crom ealkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon radical containing from 1 to 6 carbon atoms.
• Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec- butyl, isobutyl, tert-butyl, isopentyl, and the like.
• Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
• Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or “alkynyl”, respectively).
• Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3- m ethyl- 1-butynyl, and the like.
• Ci_ 6 alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above, for example, methoxy, ethoxy, and the like.
• Halo or halogen refers to bromo, chloro, fluoro, or iodo.
• Glue or “glucuronidyl” refers to glucuronide or glucuronoside group, such as ⁇ -D-glucuronide. That is any glucuronic acid group bound by a glycosidic bond, for example, a ⁇ -glycosidic bond.
• the "Glue” group can be attached to a compound of structure (I) through any hydroxyl or carbonyl group.
• substituted as used herein (for example, in the context of a substituted heterocyclyl or substituted aryl) means that at least one hydrogen atom is replaced with a substituent.
• Ri is methyl or hydroxymethyl.
• R 2 is ethyl
• R 3 and R4 are each independently H, methyl, or glucuronidyl. In another embodiment of structure (I), R 3 and R 4 are each independently H or methyl.
• X 0 or -OH.
• the compound is selected from one llowing:
• the compounds of the present invention have purities of at least about 99.5%. In a further embodiment, the compounds of the present invention have purities of at least about 99%. In still further embodiment, the compounds of the present invention have purities of at least about 98.5%. In still other embodiments, the compounds of the present invention have purities of at least about 98%. In yet other embodiments, the compounds of the present invention have purities of at least about 95%.
• the compounds of the present invention have higher aqueous solubilities than previously synthesized PDE10 inhibitors, for example those of U.S. Pat. Nos. 8,343,970 and 8.685.975, yet have similar levels of biological activity.
• the compounds of the present invention have aqueous solubilities at least about 1.5-fold higher than previously synthesized PDE10 inhibitors.
• the compounds of the present invention have aqueous solubilities at least about 2-fold higher than previously synthesized PDE10 inhibitors.
• the compounds of the present invention have aqueous solubilities at least about 5-fold higher than previously synthesized PDE10 inhibitors.
• the compounds of the present invention have aqueous solubilities at least about 10-fold higher than previously synthesized PDE10 inhibitors.
• the compounds of the present invention may generally be utilized in the form of a free base.
• the compounds of this invention may be used in the form of an acid addition salt.
• Acid addition salts of the free base form of the compounds of the present invention may be prepared by methods well known in the art, and may be formed from reaction of the free base with organic or inorganic acids.
• Suitable organic acids include, for example, maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
• Suitable inorganic acids include, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
• Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like).
• the term “pharmaceutically acceptable salt” of structure (I) is intended to encompass any and all acceptable salt forms.
• prodrugs are also included within the context of this invention.
• Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
• Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
• Prodrugs include, for example, compounds of this invention wherein, for example, the hydroxys are bonded to any group that, when the compound is administered to a patient, cleaves to re-form the hydroxy.
• representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I).
• Alcohol protecting group chemistry is well known in the art. For example, in forming an acetate prodrug of an alcohol, one may react the alcohol with an acyl chloride and a base.
• the invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of isolated or substantially pure compounds of structure (I) being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
• isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
• radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
• Certain isotopically-labelled compounds of structure (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Substitution may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Isotopically-labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.
• the compounds of structure (I) have a chiral center, and may occur as racemates, racemic mixtures, or as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
• compositions containing one or more isolated or substantially pure compounds of structure (I) are disclosed.
• the compounds of the present invention may be formulated as pharmaceutical compositions.
• Pharmaceutical compositions of the present invention comprise one or more compounds of the present invention and at least one pharmaceutically acceptable carrier and/or diluent.
• the PDE10 inhibitor is present in the composition in an amount which is effective to treat a particular disorder - that is, in an amount sufficient to achieve desired PDE10 inhibition, and preferably with acceptable toxicity to the warm-blooded animal.
• the pharmaceutical compositions of the present invention may include a PDE10 inhibitor in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
• a typical daily dosage might range from about 1 g/kg to 100 mg/kg, preferably 0.01-100 mg/kg, more preferably 0.1-70 mg/kg, depending on the type and severity of the disease whether, for example, by one or more separate administrations. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs.
• other dosage regimens may be useful. The progress of this therapy can be monitored by standard techniques and assays.
• the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
• compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
• the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a PDE10 inhibitor, diluents, dispersing and surface active agents, binders, and lubricants.
• PDE10 inhibitor in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
• the present invention provides a method for treating diseases such as (but not limited to) psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia, delusional disorders, bipolar disorders, post-traumatic stress disorders, drug-induced psychosis, panic disorders, obsessive-compulsive disorders, attention-deficit disorders, disruptive behavior disorders, autism, depression, dementia, cognitive disorders, epilepsy, insomnias and multiple sclerosis as discussed above.
• diseases such as (but not limited to) psychotic disorders, anxiety disorders, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia
• Such methods include administering a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition.
• "treat” includes prophylactic administration.
• Such methods include systemic administration of a PDE10 inhibitor of this invention, preferably in the form of a pharmaceutical composition as discussed above.
• systemic administration includes oral and parenteral methods of administration, including subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraarticular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, intravenous, intradermal, inhalational, transdermal, transmucosal, and rectal administration.
• suitable pharmaceutical compositions of PDE10 inhibitors include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives and excipients.
• the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the PDE10 inhibitor, buffers, antioxidants, bacteriostats, and other additives and excipients commonly employed in such solutions.
• compositions of the present invention may be carried in a delivery system to provide for sustained release or enhanced uptake or activity of the therapeutic compound, such as a liposomal or hydrogel system for injection, a microparticle, nanoparticle, or micelle system for oral or parenteral delivery, or a staged capsule system for oral delivery.
• a delivery system to provide for sustained release or enhanced uptake or activity of the therapeutic compound, such as a liposomal or hydrogel system for injection, a microparticle, nanoparticle, or micelle system for oral or parenteral delivery, or a staged capsule system for oral delivery.
• compounds of structure (I) are expected to avoid or reduce metabolic side effects associated with conventional antipsychotics, in particular the incidence of therapeutically induced obesity.
• conventional antipsychotics for example, chronic use of olanzapine (Zyprexa®), the most widely prescribed medication to treat schizophrenia, and related atypical antipsychotics is associated with significant metabolic side effects including obesity and associated conditions such as diabetes.
• subchronic treatment with olanzapine stimulates food intake and increases body weight, consistent with human situations.
• olanzapine acutely lowers blood leptin levels.
• Leptin is a satiety hormone produced from adipose tissues, and decrease of leptin level stimulates appetite.
• olanzapine could stimulate food intake at least partly by reducing leptin levels.
• Acute administration of olanzapine also changes the animal's response in glucose and insulin levels in glucose tolerance tests, which may also be directly linked to olanzapine's effect in food intake and body weight gain.
• Examination of the acute effect of PDE10 inhibitors of the present invention on metabolism, such as leptin, insulin and glucose changes during a metabolic challenge in standard animal models, as well as the chronic effect of PDE10 inhibitors of the present invention in food intake, body weight and energy homeostasis, in comparison with olanzapine should provide evidence to the pharmaceutical advantage of PDE10 inhibitors as antipsychotics in terms of less side- effect concerns.
• compositions of the present invention may be administered in combination with one or more additional therapeutic agents, in combination or by concurrent or sequential administration.
• additional agents i.e., adjuvants
• Compounds of this invention may be assayed to determine their IC 50 values by a modification of the two-step method of Thompson and Appleman (Biochemistry 10; 311-316; 1971).
• cAMP is spiked with ( 3 H)cAMP and incubated with PDE10 and various concentrations of a compound of structure (I). After the appropriate incubation time, the reaction is terminated by heating. The mixture is then subjected to treatment with snake venom phosphatase. The phosphatase hydrolyzes any AMP in the mixture, but leaves unreacted cAMP intact.
• the percent of inhibition can be determined.
• IC 50 values can be calculated by performing the experiment at several concentrations using standard graphical means. A detailed description of the actual technique used for IC 50 assays as set forth in following Examples. To this end, PDE10 inhibitors of the invention have an IC 50 of ⁇ or less, generally less than 10 ⁇ , and typically less than 1 ⁇ .
• the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the following examples.
• the following examples are provided for purposes of illustration, not limitation.
• Reagents were purchased from the commercial sources and were used as received. 1H MR spectra were obtained on a Bruker AVANCE 300 spectrometer at 300 MHz and a Bruker AVANCE 400 spectrometer at 400 MHz with tetramethylsilane used as an internal reference. 13 C NMR spectra were obtained on a Bruker AVANCE 400 spectrometer at 100 MHz with the solvent peak used as the reference. Thin-layer chromatography (TLC) was performed using Whatman No. 4500-101 (Diamond No. MK6F silica-gel 60 A) plates. Visualization of TLC plates was performed using UV light (254 nm).
• reaction mixture was diluted with CH 2 C1 2 (50 mL), washed with aqueous NaHC0 3 solution (2 x 20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na 2 S0 4 and was concentrated under reduced pressure to afford crude.
• the reaction mixture was cooled to -78 °C and BF 3 » OEt 2 (0.012 g, 0.09 mmol) was added dropwise over 20 min and stirred for 1 hour at the same temperature.
• the reaction mixture was stirred for 16 hours at room temperature.
• the reaction mixture was diluted with CH 2 C1 2 (15 mL).
• the organic layer was filtered through a Celite®bed.
• the organic layer was washed with aqueous NaHC0 3 (15 mL), water (10 mL) and brine (10 mL).
• the organic layer was dried over anhydrous Na 2 S0 4 and was concentrated under reduced pressure to afford the crude product.
• reaction mixture was diluted with MeOH (5.0 mL) and the pH was adjusted to 6 with Amberlyst-15 ion exchange resin. The reaction mixture was filtered. The filtrate was concentrated to afford crude residue which was purified with prep HPLC.
• reaction mixture was quenched with HC1 (1 N, 10 mL) and was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (100 mL).
• Solubility of each compound was measured by adding 4 ⁇ of a 10 mM DMSO compound stock to 396 ⁇ buffer (either a simulated Gastric Fluid pH 1.2 (0.2% NaCl, 0.7% HC1) or simulated Intestinal Fluid pH 7.5 (0.68% KHP0 4 , pH with NaOH)). This was shaken for 24 hours at room temperature, spun at 14,000 rpm for 5 minutes, and the supernatant was transferred into a clean eppendorf tube. The absorption spectra of the compound-containing supernatant were measured from 220 to 400 nm and compared with the absorption spectra of a 10 ⁇ acetonitrile stock of the same compound. The concentration of the compound in the supernatant was calculated by comparing the absorbance maximum of the compound in the simulated buffer to that in acetonitrile.
• PDE phosphodiesterase activity
• SPA scintillation proximity assay
• Purified PDE10 was stored in 40 mM Tris-Cl (pH 8.0)/100 mM NaCl/0.04% Tween-20/20% Glycerol/3 mM DTT and then used to prepare a lOx PDE solution in 50 mM Tris-Cl (pH 7.5)/8.3 mM MgCl 2 /1.7 mM EGTA.
• Assays contained (final concentrations): 50 mM Tris-Cl (pH 7.5)/8.3 mM MgCl 2 /1.7 mM EGTA/0.5 mg/ml BSA/1% DMSO and 2 ng PDE10 in a final volume of 0.1 mL. Inhibition was evaluated at 8 concentrations in duplicate. Reactions were initiated by addition of enzyme and were terminated after 20 minutes at 30 °C by the addition of 50 ⁇ of SPA beads containing Zn ++ . The mixture was shaken, allowed to settle for at least 1 hour, and counted in a Wallac plate counter. Results (net cpm) were fitted to a four parameter logistic model using Excel Solver ® .
• compounds of this invention are PDE10 inhibitors with an
• IC50 100 ⁇ or less, generally less than 10 ⁇ , and typically less than 1 ⁇ .
• Compounds 1, 2, 3, and 4 for example, were found to have IC 50 values of less than or equal to 1 ⁇ .

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• 2016
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